Male Reproductive Tract

Long-Term Continuous Treatment with Sildenafil Ameliorates Aging-Related Erectile Dysfunction and the Underlying Corporal Fibrosis in the Rat

Abstract
Aging-related erectile dysfunction is characterized by a loss of smooth muscle cells (SMC) and fibrosis in the corpora cavernosa, and functionally by corporal veno-occlusive dysfunction (CVOD). PDE5 inhibitors, in part via upregulating inducible nitric oxide synthase (NOS2A), have anti-fibrotic properties in penile tissues. We aimed to determine whether in the aged rat the chronic long-term treatment with sildenafil ameliorates corporal SMC loss and fibrosis, stimulates NOS2A induction, and corrects the associated CVOD. Aged male (20 month old) rats received sildenafil in their drinking water (20 mg/day/kg) or plain water for 45 days, and untreated young rats (5 months old) served as controls (n=8/group). CVOD was assessed by dynamic infusion cavernosometry (DIC). Collagen/SMC (Masson's trichrome) and collagen III/I (picrosirius red) ratios, SMC content (alpha-smooth muscle actin, ACTA2), cell proliferation (proliferating nuclear antigen, PCNA), apoptotic death (TUNEL), and NOS2A induction, were measured by histo- and immunohistochemistry followed by quantitative image analysis. Collagen content was determined by hydroxyproline assay, and transforming growth factor beta1 (TGFB1), xanthine oxidoreductase (XDH), ACTA2, NOS2A, the Rho kinase inhibitor, PTPN11, and activator, VAV, were measured by quantitative western blot. In the aged rats treated with sildenafil, the erectile response by DIC was normalized and the corporal SMC/collagen ratio and SMC number were increased. In addition, sildenafil reduced the corporal collagen content without affecting the collagen III/I ratio, increased the PCNA/apoptosis ratio, and stimulated NOS2A induction, although there was no effect on XDH, TGFB1, PTPN11 and VAV levels. These data show that long-term PDE5A treatment corrected CVOD in the aged rat and partially reversed the aging-related fibrosis and loss of SMC in the corpora cavernosa, without affecting a marker of oxidative stress, TGFB1 or PTPN11 levels. It may be speculated that similar effects may be achieved with this paradigm in men.

Key words: Aging • Apoptosis • Nitric oxide • Penis • Phosphodiesterases

This article has been cited by other articles:

				A. L. Burnett Molecular Pharmacotherapeutic Targeting of PDE5 for Preservation of Penile Health J Androl, January 1, 2008; 29(1): 3 - 14. [Abstract] [Full Text] [PDF]